Submissions for variant NM_032043.3(BRIP1):c.2216T>C (p.Leu739Pro)

dbSNP: rs587780234

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116136	SCV000150045	uncertain significance	not provided	2014-02-12	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.2216T>C at the cDNA level, p.Leu739Pro (L739P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Leu739Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRIP1 Leu739Pro occurs at a position that is well conserved across species and is located in the helicase domain (Cantor 2011). In addition, in silico algorithms predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRIP1 Leu739Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526865	SCV000633596	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-06-04	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is present in population databases (rs587780234, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 739 of the BRIP1 protein (p.Leu739Pro). ClinVar contains an entry for this variant (Variation ID: 128168). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRIP1 protein function.
Fulgent Genetics, Fulgent Genetics	RCV000526865	SCV000896651	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415596	SCV002724808	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-08	criteria provided, single submitter	clinical testing	The p.L739P variant (also known as c.2216T>C), located in coding exon 14 of the BRIP1 gene, results from a T to C substitution at nucleotide position 2216. The leucine at codon 739 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.